Epilepsy
Epilepsy is a chronic neurological disorder characterized by recurrent, unprovoked seizures resulting from abnormal electrical activity in the brain. Epilepsy can significantly impair quality of life, leading to cognitive, psychological, and social challenges. It affects over 50 million people globally, making it one of the most common neurological conditions. The condition’s complexity arises from its diverse causes, including genetic factors, brain injuries, and developmental disorders. The unpredictability of seizures often leads to significant psychological, social, and cognitive challenges for those affected. Despite advancements in treatment, many patients continue to experience uncontrolled seizures and face significant side effects or develop resistance to current medications, underscoring the urgent need for more effective and safer therapies.
About Epilepsy
Epilepsy is a chronic neurological disorder that manifests through recurrent, unprovoked seizures, which is a period of behavior due to the sudden surges of excessive or synchronous neuronal activity in the brain. Most common type of seizures are convulsice seizures that involve involuntary muscle contractions, often with loss of consciousness. The classic example is the tonic-clonic seizure, where the body stiffens (tonic phase) followed by rhythmic jerking (clonic phase). There are also non-convulsive seizures, such as absence seizeure, which presents as a decreased level of consciousness and usually lasts about 10 seconds. Some individuals experience a warning sensation before a seizure, known as an aura, which can manifest as strange smells, visual disturbances, or feelings of déjà vu.
Epilepsy affects more than 50 million people worldwide, significantly impacting their quality of life. Epilepsy can manifest at any age. Each year, approximately 125,000 new individuals develop epilepsy, and 30% of them are under the age of 18. The nature of seizures is diverse, influenced by the location in the brain where the disruption originates and the extent of its spread. This can lead to temporary manifestations such as lapses in awareness or consciousness, and disruptions in movement, sensory experiences (including vision, hearing, and taste), mood, or various cognitive functions.
Causes of Epilepsy
Epilepsy can arise from various etiologies, including:
- Brain Damage: Servere head injuries, brain tumors, and brain damage from drug use or prenatal/perinatal causes can disrupt normal brain activity, leading to epilepsy.
- Genetic Factors: Some forms of epilepsy are inherited, resulting from genetic mutations that affect neuronal function.
- Metabolic Disorders: Conditions like mitochondrial diseases can impair brain function and trigger seizures.
- Infections: Meningitis, encephalitis, and other infections can cause inflammation in the brain, leading to epileptic episodes.
- Unknwons Causes: In many cases, the exact cause remains unknown, classified as idiopathic epilepsy.
Current Treatment
Epilepsy is usually a lifelong condition, but it can be controlled. The primary treatment for epilepsy is medicines—anti-epilepsy drugs. The use of anti-epilepsy drugs has been increasing rapidly, with annual growth rates ranging from 6% to 15%. The primary reason for this surge is the expanding use of these drugs for conditions other than epilepsy.
Widely used anti-epilepsy drugs include:
- Carbamazepine, effective for focal and generalized tonic-clonic seizures but associated with side effects like dizziness and drowsiness;
- Valproate, used for various seizure types but posing risks for liver toxicity and teratogenic effects;
- Lamotrigine, known for its broad-spectrum efficacy and relatively favorable side effect profile; and
- Levetiracetam, increasingly popular due to its safety and tolerability with fewer drug interactions.
Despite the availability of these medications, significant gaps remain in epilepsy treatment. Approximately one-third of patients do not achieve adequate seizure control with current medications, necessitating new therapeutic approaches. Many AEDs cause adverse effects that can impair daily functioning and overall well-being, highlighting the need for drugs with better tolerability.
Novel Approch for the Treatment of Temporal Lobe Epilepsy
Temporal lobe epilepsy
Temporal lobe epilepsy (TLE), one of the most common forms of epilepsy, is associated with focal seizures originating from the temporal lobe. presents a significant challenge in the field of neurology, characterized by recurrent focal seizures originating in the temporal lobe. There are two primary forms of TLE: mesial temporal lobe epilepsy (MTLE) and lateral temporal lobe epilepsy (LTLE). MTLE is particularly associated with hippocampal sclerosis, which involves the loss of neurons in key hippocampal regions such as cornu ammonis region 1 (CA1) and the dentate gyrus (DG).
The precise mechanisms underlying the abnormal brain activity in TLE remain incompletely understood. However, animal models of epilepsy, such as the kainic acid (KA) model, have provided valuable insights into the mechanisms underlying the generation and propagation of seizures. Status epilepticus (SE), a prolonged seizure activity, can be induced by agents like kainic acid (KA), which affects ionotropic KA receptors in regions such as the amygdala, hippocampus, and entorhinal cortex. This results in specific brain lesions that mimic human epilepsy.
Relationship between synaptic plasticity and epilepsy
Recent research has shed light on the relationship between synaptic plasticity, particularly long-term potentiation (LTP), and the pathogenesis of epilepsy, opening new avenues for therapeutic intervention.
The precise excitation and inhibition (E-I) balance in the cortical network is crucial for proper brain function, including processes like short-term and long-term memory. Alteration of E-I balance can lead to epilepsy. Epilepsy, in particular, is associated with abnormal synaptic function and neurotransmitter release, highlighting its multifactorial nature. The concept of synaptic plasticity, which is essential for normal development and function, plays a critical role in the pathogenesis of epilepsy. Induciton of hippocampal epilepsy though the kindling mode have demonstrated the relationship between long-term potentiation (LTP) and epilepsy. Studies have shown that NMDA antagonists can partially block LTP induction and reduce the effects of kindling-induced afterdischarges.
Exploring a Novel Therapeutic Approach for Temporal Lobe Epilepsy
Our novel GPCR antagonist, Neu-003, has demonstrated the ability to suppress LTP in preclinical studies, suggesting its potential as an anti-epileptic agent. By selectively blocking the target GPCR, our drug candidate can help restore the E-I balance in the brain, reducing the likelihood of seizures. Additionally, our compound has shown favorable pharmacokinetic properties, including good oral bioavailability and brain penetration, which are essential for effective drug delivery to the central nervous system.
Neu-002 represents a promising new approach to treating epilepsy by suppressing LTP and modulating the E-I balance in the brain. By targeting a specific GPCR involved in regulating neuronal excitability and synaptic transmission, our drug candidate has the potential to provide better seizure control and improve the quality of life for patients with epilepsy. Further preclinical and clinical studies are underway to fully evaluate the safety and efficacy of this novel therapeutic agent.
Figure. Neu-003 blocked the LTP in the auditory cortex. TBS-induced LTP was successfully induced in the mouse (C57) auditory cortex during the control experiment, whereas Neu-003 blocked TBS-induced LTP in C57 cortical slices. (90 nM Neu-003; n=10 slices/4 mice). Data are expressed as mean ± SEM.
Neu-003 analog suppresses spontaneous seizures in the kainic acid induced chronic epilepsy mouse model
